The fungal metabolites called afl atoxins are potent naturally occurring carcinogens, produced primarily by Aspergillus fl avus and A. parasiticus . A. fl avus affects many agricultural crops such as maize, cotton, peanuts, and tree nuts. It can contaminate these crops with afl atoxins in the fi eld before harvest. It is a serious concern because of its toxic and carcinogenic properties and also due to the risk of contamination in food and feed on human health and livestock. It is not only a serious food safety issue, but it has signifi cant economic implications for the agricultural industry worldwide because of restrictions limiting the trade of contaminated crop. Host plant resistance is an effective, effi cient and dependable tool to protect crops from the preharvest infection and afl atoxin contamination processes. Host plant resistance to afl atoxin contamination is a complex trait, and dissecting this trait is an equally complex task. With the technological breakthrough in genomics and next-generation sequencing, our understanding on the Aspergillus biology is greatly enhanced. This chapter aggregates the rich afl atoxin literature and focuses on the factors that cause the stress execrably and increase the afl atoxin contamination of grains before and after harvest. Further discussed are potential future prevention technology and strategies that could be employed to guide future research, such as "next-generation" genetics.